belta5, 16-11, 20-diketo-16-(organic sulfonoxy)-pregnadiene-3-ketals and process



United States Patent I A -11,20-DIKETO-16-(ORGANIC SULFONOXY)-PREGNADIENE-S-KETALS AND PROCESS Glen E. Arth, Cranford, N. L, George I.Poos, Ambler, Pa., and Lewis -H. Sarett, Princeton, N. J., assignors toMerck & Co., Inc., Rahway, N. L, a corporation of New Jersey No Drawing.Application December 31, 1956 Serial No. 631,493

Claims. (Cl. 260-23955) This invention is concerned generally withdimethyl. cyclopentanopolyhydrophenanthrene compounds and with processesfor preparing them. More particularly, it relates to a novel process forpreparing A -3,11,20-triketopregnene starting withl-alkoxyethinyl-l-hydroxy-Z-methallyl-2,4b-dimethyl-4-keto-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene compounds having inthe 7-position a ketal or other substituent convertible to keto byhydrolysis, to the individual steps in this process, andto theintermediate compounds thus obtained.

This application is a continuation-impart of ,ourcopending applicationSerial Not-310,133, now'abandoned, filed September 17, 1952.

The A -3,l1,20-triketo-pregnene, which is valuable as an intermediate inthe preparation of steroid hormones such as cortisone, may be chemicallyrepresented as follows: a

The 1 alkoxyethinyl 1 hydroXy 2methallyl-2,4bdimethyl-4-keto-1,2,3,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene, having in the 7-position a ketal substituent hydrolyzableto a 7-keto grouping, used as starting material in our novel process,may be chemically represented as follows:

wherein R is alkyl, and X may be Y-L L Y and Y being hydrocarbonradicals, L and M being oxygen or sulfur, and Z being alkylene. In eachof the "ice from ring B to ring A thus forming a (1,]3-11I1S3tl11'3ti5dketone. We ordinarily prefer to utilize an ethylene-dioxy substituent asthe protecting group, and our preferred starting material is therefore1-alkoxyethinyl-l-hydroxy-2-methallyl-2,4b-dimethyl-4-keto-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene.

Utilizing the latter compound as starting material, and in accordancewith our presently invented process, l-alkoxyethinyl-l-hydroxy 2methallyl-2,4b-dimethyl-4-keto-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene(Compound 1 hereinbelow) is reacted with a dilute aqueous mineral acidsolution to produce the corresponding1-carboalkoxymethylene-Z-methallyl-Z,4bdimethyl-4-keto-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10, 10a-dodecahydrophenanthrene (Compound 2); thelatter compound is reacted with an alkaline saponifying agent therebyforming 1-carboXymethylene-2-methallyl-2,4b-dimethyl-4-keto- 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, 10a-dodecahydrophenanthrene(Compound 3). The 1- carboxymethylene-2-methallyl-2,4b-dimethyl- 4 keto7- ethylene-dioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthreneis then reacted with an alkali metal in a lower alkanol or in liquidammonia to producel-carboxymethyl-Z-methallyl-2,4b-dimethyl-4-hydroxy-7- ethyle ne diox y,-,1,,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene (Compound 4).Alternatively, this reduction operation, which involves the reduction ofboth the C-4 keto group to hydroxy and the l-carboxymethylene radical toa carboxymethyl grouping, can be carried out step-wise by reacting the1-carboxymethylene-Z-methallyl- 2,4b-dimethyl-4-keto-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene with an alkalimetal borohydride or alkaline earth metal borohydride to form thecorresponding 1rcarboxymethylene-2-methal1yl-2,4bdimethyl-4-hydroxy-7-ethylenedioxy -1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene (Compound 5); the latter compound isreacted with an alkali metal in a lower alkanol or in liquid ammonia toproduce l-carboxymethyl-2-methallyl-Z,4b-dimethyl-4-hydroxy-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene (Compound 4). Thiscompound is reacted with an esterifying agent, preferably an alkyliodide in the presence of a base and/or a diazoalkane to produce thecorresponding 1- carboalkoxyrnethyl-2-methallyl-2,4b-dimethyl-4-hydroxy-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene(Compound 6). This compound is reacted with an oxidizing agent,preferably under alkaline conditions, thereby forming the correspondingl-carboalkoxymethyl-Z-methallyl 2,4b-dimethyl-4-keto-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenan threne (Compound 7);alternatively, 1-carboxymethyl-2- methallyl 2,4b-dimethyl4-hydroxy-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene can be reacted with anoxidizing agent to producel-carboxymethyl-2-methallyl-2,4b-dirnethyl-4-keto-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene (Compound 8-),which is then reacted with an esterifying agent; to form thecorresponding l-carboalkoxymethyl-Z- methallyl-2,4b-dimethyl-4-keto-7-'ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene(Compound 7). The latter compound is reacted with osmium tetroxide toform the osmate ester of l-carboalkoxymethyl-Z- (beta,gamma-dihydroxyisobutyl -2,4b-dimethyl- 4 keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene (Compound 9), whichis reacted with an aqueous alcoholic solution of an alkali metal sulfiteor bisulfite to produce the corresponding 1 carboalkoxymethyl 2(beta,gamma dihydroxy-isobutyl)-2,4b-dimethyl-4-keto-7 ethylenedioxy1,2,3,4,4a, 4b,5,6,7,8,10,10a dodecahydrophenanthrene compound (Compound10); the 1-carboalkoxymethyl-2-(beta,gamma-'dihydroxyisobutyl)-2,4b-dimethyl-4-keto-7-ethylenedioxying A-3-ethy1enedioxy-11,16,2O-triketo-pregnene (Com- 15 ,4 pound 12). The A-3-ethylenedioxy 11,16,20 triketo pregnene is reacted with an organicsulfonyl halide thereby forming the corresponding sulfonate ester of A-3- ethylenedioxy 11,20 diketo 16 hydroxy pregnadiene (Compound 13),which is reacted with hydrogen in the presence of a hydrogenationcatalyst to produce A -3- ethylenedioxy-l 1,20 diketo pregnene (Compound14). The A -3-ethylenedioXy-11,20-diketo-pregnene is then reacted withan aqueous mineral acid solution whereupon the ethylenedioxy substituentattached to the 3-carbon atom is hydrolyzed and, at the same time, thedouble bond shifts from ring B to ring A to form (X -3,11,20-triketo-pregnene (Compound 15).

The reactions indicated herein above may be chemically represented asfollows:

(3H3 CH (3H1 $=CH2 C|1=CH2 (iJ=CH O: l CHz 0: CHz 0: CH2

:CEC-OR =CH.COOR ==CHCOOH O O O Compound 1 Compound 2 Compound 3 (EH:(3H3 3 Cl=CH2 C|l=CH1 (]]=CH2 Ho CH: HO CHz Ho /CH2 =CH-CO0H CH1COOH-CH2COOR Compound 5 Compound 4 Compound 6 (EH; (EH3 (IJ=CH1 (il cHa 0:/CH2 0: /CHZ CH2C0OH CHZCOOR' Compound 8 Compound 7 1 l CHz-O 0504 CHzOHCH3 CH -(JO CH3(|JOH (|,=O O- /CH1 0: /CH2 Ozfi /CH2 -CHzCOOR' CH2C0ORCH2CO0R O O O l Compound 9 Compound 10 Compound 11 Compound 12 Compound13 [ZQU i Compound Compound 14 wherein R and R are alkyl radicals and R"is an organic procedure to produce 5-methyl-6-ethoxy-1,4,4a,5,8,8a-

radical.

Although in the foregoing series of reactions, the substituent in ring Aof the polyhydrophenanthrene nucleus is shown as an ethylenedioxygrouping, instead of ethylenedioxy, any ketal substituentincludingsimple ketals, thioketals, hemithioketals, cyclic ketals, cyclicthioketals, and cyclic hemithioketals can be used as the protectinggrouping. In place of a ketal substituent, an enol-ether may be used asthe protecting group, if desired. Accordingly, instead ofl-alkoxyethinyl-l-hydroxy- 2-methallyl-2,4b-dimethyl-4-keto-7ethylenedioxy 1,2,3,

4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene, any 1--alkoxyethinyl-Z-(allyl or alkallyl)-2,4b-dimethyl-4-keto-1,2,3,4,4a,4b,5,6,7,8,10,10a d o d e cahydrophenanthrene compound,having in the 7-position a ketal substituent (including simple ketals,thioketals, hemithioketals, cyclic ketals, cyclic thioketals, and cyclichemithioketals) hydrolyzable to a 7-keto grouping, may be used asstarting material in the presently invented process. In each of theprocess operations utilized by us in preparing A -3,11,ZO-triketo-pregnene, the keto group in ring A is blocked by a ketalprotecting group (as above defined). At any stage in the process, thisketo group may be regenerated by acid hydrolysis whereby the ketal groupis hydrolyzed and, at-the same time, the double bond shifts from ring Bto ring A thus forming an a,fl-unsaturated ketone. It is ordinarilypreferred to utilize an ethylenedioxy substituent as the protectinggroup, and our preferred starting material is1-alkoxyethinyl-1-hydr0Xy-2 methallyl 2,4b di methyl 4 keto 7ethylenedioxy 1,2,3,4,4a,5,6,7,8,l0, 10a-dodecahydrophenanthrene.

This 1 -al koxyethinyl 1-hydroxy-2-methallyl-2,4b-dimethyl-4-keto-7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, 10a-dodecahydrophenanthrene is anew compound which may be prepared according to the following procedure:fl-ethoxy-propionaldehyde is reacted with ethyl magnesium bromide toproduce 1-ethoxy-3-hydroXy-pentane which is reacted with chromic acidthereby oxidizing the hydroxy substituent to form1-ethoxy-3-keto-pentane; the latter compound is treated with ethyl orthoformate and ethanol in the presence of hydrogen chloride to produce1,3,3-triethoxy-pentane which, upon reaction with hot potassiumbisulfate, is converted to 3-ethoxy-1,3-pentadiene. The3-ethoxy-1,3-pentadine is reacted with homequinone in accordance withthe Diels-Alder condensation hexahydronaphthalene-1,4-dione which isthen reacted with hydrogen in the presence of Raney nickel catalyst i toform 5-methyl-6-ethoxy-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1,4-dione;the latter compound is reacted with lithium aluminum hydride to form thecorresponding diol,S-methyl-G-ethoxy-l,2,3,4,4a,5,8,8a-octahydronaphthalene-1,4-diolwhichis reacted with a hydrolyzing agent to produce5-methyl-6-ketoperhydr0naphthalene-1, 4-diol. The reactions indicatedabove are described in detail in a co-pending application of one of thepresent applicants, Serial No. 216,109, now abandoned, filed March 16,1951. The 5-methyl-6-keto-perhydronaphthalene-1,4-diol is then reactedwith N-(3-keto-butyl)-N,N- diethyl-N-methylammonium' iodide in thepresence of potassium hydroxide to produce 7-keto-4b-methyl-l,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-1,4- diol; this reactionis described in detail in co-pending application, Serial No. 228,126,filed May 24, 1951, now U. S. Patent No. 2,617,828. The 7-keto-4b-methyl-1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-1,4-diol is reacted withethylene glycol in ethylene dichloride solution and in the presence ofp-toluene sulfonic acid catalyst thereby forming 1,4 dihydroxy 4bmethyl-7-ethylene-' dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10ad'odecahydrophenan- The 1,4-dihydroxy-4b-methyl-7 ethylenedioxy Ithrene. 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene is reactedwith cyclohexanone and aluminum isopropoxide in benzene solution toproduce the corresponding l-keto- 4-hydroxy-4b-methyl-7 ethylenedioxy1,2,3,4,4a,4b,5,6, 7,8,10,10a-dodecahydrophenanthrene. The reactionsindicated hereinabove are described in detail in a co-pendingapplication of the present applicants, Serial No. 286,808, nowabandoned, filed May 8, 1952.

The 1-keto-4-hydroxy-4b-methyl-7-ethylenedioxy-l,2,- I3,4,4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene is reacted with methyliodide in the presence of potassium tertiary butoxide in benzene therebyforming 1-keto-2,4bdimethyl-4-hydroxy-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,- 8,l0,10a-clodecahydrophenanthrene; the lattercompound is reacted with chromium trioxide-pyridine complex to form1,4-diketo-2,4b-dimethy1-7-ethylenedioxy-l,2,3,4,4a,-

4b,5,6,7,8,10,10a-dodecahydrophenanthrene. The methylation reactionindicated hereinabove is described in detail inaco-pendingapplication inwhich one of the present applicants is co-inventor, Serial No. 306,488,now abandimethyl-4-keto' 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,-

10,1 Oa-dodecahydrophenanthrene.

Alternatively, the 1 keto 2,4b-dimethyl-4-hydroxy-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene isreacted with methallyl iodide in a tertiary butyl alcohol solution ofaluminum tertiary butylate to produce 1-keto-2-methallyl-2,4b dimethyl 4hydroxy-7- ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,l0,ladodecahydrophenanthrene which, upon reaction with an alkoxy acetylenemagnesium bromide in ether-benzene solution, is converted to thecorrespondingl-alkoxyethinyl-l,4,-dihydroxy-Z-methallyl-2,4b-dimethyl-7-ethylenedioxy1,2,3,- 4,4a,4b,5,6,7,8,l0,l0a-dodecahydrophenanthrene. The reactionsindicated hereinabove are described in detail in two copendingapplications of the present applicants, Serial No. 306,509, nowabandoned, filed August 26, 1952, and Serial No. 308,172, now abandoned,filed September 5, 1952. Where it is desired to utilize another cyclicketal or other ketal substituent (as defined above) or an enol-ethersubstituent to protect the 7-keto grouping, this is introduced in theforegoing procedure by reacting the intermediate1,4-dihydroxy-7-keto-4b-methyll,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthreneunder substantially anhydrous conditions'and in the presence ofan acidcatalyst, with a lower alkanol such as an excess amount of methanol,ethanol, propanol, butanol, and the like, or an excess of another lowmolecular weight glycol such as propylene glycol, butylene glycol, or anexcess of a thioglycol or dithioglycol such as ethanedithiol,propane-1,2, dithiol, ,8 mercapto-ethanol, fl-mercaptopropanol, and thelike. If it is desired to use an enolether as the protecting group, thel,4-dihydroxy-7-keto- 4b methyl l,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene is reacted, under substantially anhydrousconditions in the presence of an acid catalyst with an 'alkyl orthoformate.

The rearrangement of the l-alkoxyethinyl-l-hydroxy-2-methallyl-2,4b-dimethyl-4-keto-7-ethylenedioxy 1,2,3,-4,4a,4b,5,6,7,8,l0,l0a-dodecahydrophenanthrene, its 2- allyl andZ-alkallyl ho-molog, and other 7-ketals thereof, is carried out bybringing this compound into intimate contact with an aqueous mineralacid in solution in an organic solvent for the compound, for example acyclic ether such as tetrahydrofuran, tetrahydropyran, dioxane or analkanol such as ethanol, isopropanol, butanol and the like, under whichconditions the ketal or enol ether substituent attached to theC-7-carbo'n atom is not appreciably hydrolyzed. We ordinarily utilizetetrahydrofuran as the organic solvent in conjunction with aqueoussulfuric acid solution, and allow the slightly exothermic reaction whichtakes place to proceed at a temperature of about 2530 C. Under theseconditions, the reaction is ordinarily complete in about three andonehalf hours. In accordance with this procedure, there is obtained thedesired l-carboalkoxymethylene-2-methallyl- 2,4b-dimethyl-4-keto 7ethylenedioxy l,2,3,4,4a,4b,5,- 6,7,8,l0,lOa-dodecahydrophenanthreneadmixed with a lay-product, l-carboalkoxymethyl-1-hydroxy-2-methyl-2,-4b-dimethyl-4-keto-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,-8,10,l0a-dodecahydrophenanthrene. These two products can be convenientlyisolated from the reaction mixture by neutralizing the mineral acid witha mildly aqueous alkaline solution, preferably a saturated aqueoussolution of sodium bicarbonate, distilling the organic solvent underreduced pressure, and extracting the oil which separates duringdistillation into the ether. After washing, drying and evaporating-theether extract, there is obtained a residual oily material from which itis possible to fractionally crystallize the foregoing components insubstantially pure form. It is ordinarily preferred, however, toseparate these two products in pure form by chromatography onaeid-Washed'alumina. This is accomplished by dissolving the residualoily material in benzenepetrolcum ether, contacting this solution withacid-washed alumina and eluting the adsorbate with a mixture ofpetroleum ether-ether. From the eluates richer in the petroleum ethercomponent is obtained thel-carboalkoxymethylene-2-methallyl-2,4b-dimethyl-4-keto-7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene and from thefollowing fractions which contain a relatively higher proportion ofether is obtained the lcarboalkoxymethyl 1 hydroxy 2 methallyl 2,4bdimethyl-4-keto-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,-10a-dodecahydrophenanthrene.

The saponification of the ester grouping in thel-carboalkoxymethylene-2-methallyl-2,4b-dimethyl 4 keto 7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene isconducted utilizing an alkaline hydrolyzing agent since the 7-positionsubstituent is unstable under the conditions normally encountered in theacid hydrolysis of esters. The hydrolysis is conveniently carried oututilizing an aqueous methanolic solution containing potassium carbonateand a small amount of potassium hydroxide, but other alkalinehydrolyzing agents canbe utilized if desired. When this preferredhydrolyzing agent is utilized, saponification may be carried out at roomtemperature, or. more rapidly, if desired, by heatingthe reactants atthe reflux temperature of the solution. Themethanol is evaporated underreduced pressure, and the aqueous mixture diluted with approximately anequal volume of water, whereupon thepotassium salt of2-carboxymethylene-2-methallyl-2,4bdimethyl-4-keto-7-ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10, 10a-dodecahydrophenanthrene may precipitate asan oil. The aqueous solution or suspension is then extracted with ether,and the aqueous mixture is acidified with a mildly acidic reagent suchas sodium dihydrogen phospate. The acidic material which separates isextracted with chloroform, the chloroform extracts are dried andevaporated under reduced pressure to give l-carboxymethylene-2-methallyl-2,4b-dimethyl-4-keto-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,l0a-dodecahydrophenanthrene. This material may befurther purified by washing with ether and recrystallizing the materialfrom ethyl acetate.

As set forth herein above, the l-carboxymethylene-2-methallyl-2,4b-dimethyl-4-keto-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene can be converted directlyto 1-carboxymethyl-Z-methallyl-Z,4bdimethyl-4-hydroxy-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene by reaction withan alkali metal, such as sodium, lithium, or potassium, or this reactioncan be carried out in two operations, first reducing the 4-ketosubstituent to hydroxy utilizing an alkali metal borohydride such assodium borohydride, lithium borohydride, potassium borohydride or analkaline earth metal borohydride such as calcium borohydride, and thenreducing the l-carboxymethylene substitutent utilizing the alkali metal.

The reaction between the 1 carboxymethylene 2-metl1allyl-2,4b-dimethyl-4-keto-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene and the alkali metalborohydride or alkaline earth metal borohydride is conducted bysuspending the hydrophenanthrene compound in water or in aqueous organicsolvent such as aqueous tetrahydrofuran, aqueous dioxane, aqueousdioxane, aqueous alkanol, and the like, and adding thealkali metal oralkaline earth metal borohydride 9. cautiously to the mixture. After allthe reducingagent has dissolved, the resulting mixture is allowed tostand preferably at a temperature between about room tem' perature and100 C., although higher and lower temperatures may be used if desired.When the reaction is carried out at a temperature of about 30 C., thereaction is ordinarily complete after a reaction time of about 24 hours.The aqueous mixture is carefully acidified, preferably maintaining thepH about about 3.5; it is preferred to utilize sodium dihydrogenphosphate for this acidification. The product which precipitates isextracted with an organic solvent such as chloroform. The chloroformextracts are washed, dried and evaporated in vacuo to give an oil whichcan be crystallized from ether to'give crystalline 1 carboxymethylene 2methallyl 2,4b dimethyl-4-hydroxy-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene.

The latter product or, if desired, the startingl-carboxymethylene-2-methallyl-2,4b-dimethyl-4-keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10a'- dodecahydrophenanthrene is reacted withan alkali metal such as metallic lithium, sodium or potassium, and thelike, in solution in a lower alkanol and/ or in liquid ammonia.

Where metallic lithium or potassium are used as the reducing agents, itis preferred to use liquid ammonia. The reaction system which has beenfound .most advantageous is potassium-liquid ammonia-isopropanol. Thereaction between the 1-carboxymethylene-2-methallyl-2,4b-dimethyl-4-(keto or hydroxy)-7-ethylenedioxy-l,2,3,4,4a,5,6,7,8,l0,lOa-dodecahydrophenanthrene and metallic lithium orpotassium is conveniently carried out by suspending thehydrophenanthrene compound in liquid ammonia and adding the alkali metalportion-wise to the suspension. If desired, a lower alkanol such asethanol, butanol, and the like may be added to the reaction mixture;although the reduction reaction will occur in the absence of thealkanol, the yield of the desired product is improved, in some cases, bythe use of the alkanol. The liquid ammonia reaction mixture is stirredat the boiling point of liquid ammonia until the ammonia has evaporated.The crude reaction mixture is treated with benezene, and, if necessary,a small amount of ethyl acetate or alcohol is added to destroy theexcess alkali metal. The resulting mixture is then diluted with water,the benzene layer is discarded, and the alkaline layer containing thereduction product is solidified. The material which precipitates isextracted with chloroform, and the chloroform extract is washed, driedand evaporated. The oily material thus obtained is crystallized byheating with ether to give crude 1-carboxymethyl-Z-methallyl-2,4b-dimethyl-4-hydroxy-7-ethylenedioxy 1,2,3,4,4a,5,6,7,8,10,10a-dodecahydrophenanthrene.

When sodium or potassium is used as the reducing agent, the reaction isconveniently carried out by bringing together the1-carboxymethylene-Z-methallyl-2,4bdimethyl-4-(keto or hydroxy)-7-ethylenedioxy-1,2,3,4,4a, 4b,5,6,7,8,10,10a-dodecahydrophenanthrene,alkali metal, and a hot lower alkanol, and stirring the resultingmixture under reflux for a period of about fifteen minutes. The recationmixture is evaporated to about one-half volume in vacuo, diluted withwater and the aqueous solution is carefully acidified. The acidicaqueous mixture is extracted with chloroform, and the chloroform extractis dried and evaporated in vacuo. The residual material consists ofcrude1-carboxymethyl-2-methallyl-2,4b-dimethyl-4-hydroxy-7-ethylenedioxyl,2,3,4,4a,5,6 ,7,8,10, 10a-dodecahydrophenanthrene.

When the reduction is carried out utilizing as starting material thel-carboxymethylene-Z methallyl 2,4b dimethyl-4-keto-7-ethylenedioxy1,2,3,4,4a,5,6,7,8,10,10adodecahydrophenanthrene, there may be obtained,in addition to the l-carboxymethyl 2 methallyl 2,4bdimethyl-4-hydroxy-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,7,10,lOa-dodecahydrophenanthrene, a small amount of 1-carboxymethyl-Z-methallyl-Z,4b-dimethyl-4-keto-7 ethyl-.

enedioxy 1,2,3,4,4a,4b,5,6,7,'8,10,10a dodecahydroph nanthrene.

Esterification of the l-carboxymethyl-2,4b-dimethyl-4- (hydroxy orketo)-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene can be carried out by any of the usualmethods of esterification but, in view of the ease of hydrolysis of themetal substituent in the 7-position, it is ordinarily preferred toconduct this esterification under alkaline conditions using adiazoalkane or an alkyl iodide in the presence of a base as theesterifying agent. The reaction utilizing a diazoalkane such asdiazomethane or diazoethane is convenientlyc'arried out by dissolvingthe 1-carboxymethyl-2-methallyl-2,4b-dimethyl- 4 (hydroxy or keto) 7ethylenedioxy 1,2,3,4,4a,4'b, 5,6,7,8,10,10a-dodecahydrophenanthrene inan organic solvent such as ether and adding to this solution an excessof the diazoalkane in an inert organic solvent medium' such as ether.The resulting solution is allowed to stand at approximately. roomtemperature until the evolution of nitrogen ceases, the solvents areevaporated, and the residual oil is crystallized to givel-carboalkoxymethyl-Z-rnethallyl-2,4b-dimethyl-4-(hydroxy or keto)-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene.

The 1-carboalkoxymethyl-2-methallyl-2,4b-dimethyl-4- hydroxy 7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,3,10,10adodecahydrophenanthrene can beconverted by reaction with an oxidizing agent to the corresponding4-keto derivative, which is alternatively obtained by the esterificationof the 1-carboalkoxymethyl-2-methallyl-2,4b-dimethyl-4- dizing agentssuch as chromic acid may be employed if desired. Using the preferredoxidant, the l-carboalkoxy- 1 methyl'-2-methallyl-2,4b dimethyl4-hydroxy-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene is dissolved in pyridine and mixed with the complex formed byadding chromium trioxide to an excess The resulting mixture is allowedto stand of pyridine. at a'temperature within the range of about 0 C. to

C. for a period of time, depending upon the temperature; at roomtemperature, the reaction is ordinarily complete in about 15 hours. Thereaction mixture is diluted with water and the aqueous solution isextracted with a water-immiscible organic solvent such as ether. Theorganic solvent extracts are washed with water, dried, and the solventevaporated. The residual oil is crystallized to give1-carboalkoxymethyl-Z-methallyl-2, 4b-dirnethyl-4-keto 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene.

Further oxidation of the latter compound converts the methylenesubstituent in the methallyl radical to a keto grouping. This can beaccomplished in a two-stop oxidation utilizing osmium tetroxide followedby periodic acid or in a single-step utilizing ozone.

methyl-Z-methallyl-Z,4b-dimethyl-4-keto-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene is dissolved in adry ether benzene solution and approxias tetrahydrofurane is added tothe reaction mixture to dissolve the osmate ester, and the latter is,reacted with a mildly alkaline hydrolyzing agent under reducingconditions such as an aqueous solution of an alkali metal Where theosmium tetroxide procedure is used, the l-carboalkoxysulfite orbisulfite. The osmium oxide which precipitates from the hydrolysis isremoved by filtration, ,and thefiltered solution is evaporated underreduced pressure. The residual oily material thus obtained is shakenwith amixture of ether and water, the ethereal'extract is washed withwater, dried and evaporated to give crystalline 1carboalkoxymethyl-Z-(beta,gamma-dihydroxyisobutyl)-2,4b-dimethyl-4-keto7 ethylenedioxy-1,2,3,4,4a, 4b,5,6,7,8,l0,l(la-dodecahydrophenanthrene.

The l-carboalkoxymethyl-2-(beta,gamma-dihydroxyisobutyl)-2,4b dimethyl 4keto-7-ethylenedioxy-l,2,3,4, 4a,4b,5,6,7,8,10,10adodecahydrophenanthrene is dissolved in an organic solvent for. thecompound for example a lower alkanol, such as ethanol, and a cyclicether, such as tetrahydrofuran and the like, and to this solution areadded pyridine and an aqueous solution of periodic acid. The glycolcleavage which takes place is.ordinarily complete in a few minutes. Thereaction mixture is diluted with water, and the aqueous reaction mixtureis extracted with an organic solvent such as ether. The organic solventextract is washed, dried, and evaporated to give an oily product whichcan be crystallized to give substantially pure l-carboalkoxymethyl-Z-acetonyl-2,4b-dimethyl 4 keto-7-ethylenedioXy-1,2,3,4,4a,4b,5,6,7,8,l0,lOa-dodecahydrophenanthrene.

When the conversion of the Z-methallyl substituent to an acetonylradical is conducted utilizing ozone instead of osmium tetroxidefollowed by periodic acid, the 1- carboalkoxymethyl 2methallyl-2,4b-dimethyl-4-keto-.

under reductive conditions either by means of a small amount of zinc andaqueous acetic acid, or catalytically by contacting the ozonide in anaqueous medium with hydrogen and a platinum catalyst. When the ozonideis reacted with zinc and aqueous acetic acid, the reaction mixture ismade slightly alkaline, filtered and the solvents evaporated therefromin vacuo at a temperature below about C. The residual material isextracted with ether, the ethereal solution is chromatographed on theether-petroleum ether eluate, there is obtained l-carboalkoxymethyl 2acetonyl 2,4b dimethyl-4-keto-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene.

We then prepare a subsubstantially anhydrous solution of 1carboalkoxymethyl-2-acetonyl-2,4b-dimethyl-4- keto 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene in an aromatichydrocarbon such as benzene, toluene, and the like. This solution isbrought into contact with a solid anhydrous, strongly basic material,for example an allkali metal alkoxide, such as sodium methoxide,potassium t-butoxide, an alkali metal, such as metallic sodium, analkali metal hydride, such as sodium hydride, an alkali metal amide suchas sodamide, and the like. The resulting mixture is ordinarily stirredat a temperature within the range of about 20 to C. althoughtemperatures somewhat below or above this range may be used, if desired.When the reaction is carried out at about room temperature, thecyclization is substantially complete in approximately ten hours. Thereaction mixture is poured into water and immediately acidified with anexcess of a mildly acidic reagent such as an aqueous solution of primarysodium phosphate. The acidified solution is extracted with an organicsolvent such as chloroform and the solvent extract dried, filtered andevaporated to. give 12 crystalline A -3-ethylenedioxy-11,16,20-triketopregnene, which can be further purified if desired by recrystallization.Acid hydrolysisof the A -3-ethylenedioxy-l1,16,20- triketo-pregnenegives A -3,1l,16,20-tetraketo-pregnene.

The A -3-ethylenedioxy-1l, 16,20 triketo pregnene is then reacted withan organic sulfonyl chloride, preferably p-toluene. sulfonyl chloride.This reaction is carried out dissolving the pregnene compound in atertiary amine such aspyridine and adding the organic sulfonyl chlorideto the resultingsolution. The reaction is allowed to proceed at aboutroom temperature under whichconditions the reaction isordinarilycomplete in about twelve to twenty-four hours. The excess organicsulfonyl chloride and pyridine are neutralized ,by the addition of amildly alkaline aqueous solution such as aqueous sodium bicarbonate,andthe resulting mixture is agitated for a short period of time, duringwhich time the sulfonate crystallizes. An organic solvent such asbenzene is added to the reaction mixture, the mixture is poured into icewater, and the organic layer is separated. The organic layer is washedwith water, dried and evaporated in vacuo. The residual material can bepurified by recrystallization to give the l6-sulfonate ester of A 3-ethylenedioxy-16-hydr0xy-11,20 diketo pregnadiene in substantially pureform.

The catalytic hydrogenation of the latter material is convenientlycarried out by dissolving the 16-sulfonate ester of A-3-ethylenedioxy-l6-hydroxy-11,20-diketopregnadiene in benzene, adding ahydrogenation catalyst, such as palladium on barium carbonate, andcontacting the mixture with hydrogen at atmospheric pressure, orpreferably at superatrnosphen'c pressure. When the hydrogenationreaction is carried out at room temperature and at a pressure of aboutforty pounds per square inch, the reaction is substantially complete inabout twenty hours. It is ordinarily preferred to add additional amountsof catalyst during the course of the hydrogenation. The hydrogenationmixture is filtered, and the filtered solution is evaporated in vacuo.The residual oil is crystallized to give substantially pure A-3-ethylenedioxy-l1,20-diketo-pregnene.

The latter compound is treated with a hydrolyzing agent, preferably anaqueous mineral acid such as hydrochloric acid, perchloric acid,p-toluenesulfonic acid, and the like, thereby hydrolyzing the ketalsubstituent in the 3-position of the molecule. When aqueous perchloricacid is employed, the hydrolysis is conveniently carried out bydissolving the A -3-ethylenedioxy-11,20- diketo-pregnene in an organicsolvent such as tetrahydrofuran, adding a dilute aqueous solution ofperchloric acid to the resulting solution, and allowing the resultingmixture to stand at about room temperature for a period of about threeto four hours. The solvents are evaporated in vacuo, and the residualmaterial is extracted with an organic solvent such as chloroform. Thechloroform extract is dried, the chloroform evaporated in vacuo, and theresidual material. is crystallized to give substantially pure A-3,11,20-triketo-pregnene.

The stereoisomeric form of A -3,l1,20-triketo-pregnene having a meltingpoint of about 175176 C. possesses the eteroisomeric configurationcharacteristic of the naturally-occurring steroid hormones such asprogesterone. We refer to this stereoisomer by. the name of ll-ketoprogesterone. This compound is obtained in the form of a racemic mixtureof the dand l-forms, and referred to more specifically asdl-l1-ketoprogesterone.

The 3-ethylenedioxy derivative of dl-A -3,l1,2O-triketopregnene ofmelting point l176 C. obtained as here'- inabove described may beconverted to the therapeutically active material3,11,20-triketo-17u-hydroxy-2l-acetoxy- A -pregnene as follows:dl-3-ethylenedioxy-11,20-diketo- A -pregnene is treated with dimethyloxalate and then with alkali. to form the C-2l oxalyl acid derivative.Onformation of the strychnine salts of the components of 13 this racemicmixture the d-salt precipitates and may be recovered by filtration. ninesalt and hydrolysis of the C-21 oxalyl acid group yields3-ethylenedioxy-11,20-diketo-A -pregnene identical with that obtainedfrom naturally occurring materials.

Iodination under alkaline conditions of the natural isomer of the2l-oxalyl acid of 3-ethylenedioxy-11,20- diketo-A -pregnene, which maybe obtained in the above described resolution procedure, yields3-ethylenedioxy- 17a-hydroxy-2l-acetoxy-A pregnene by the procedurehereinabove described. a I

In addition to being useful as an intermediate in the to-. tal synthesisof cortisone acetate, dl-ll-keto-progesterone has been shown to possessgreater cortisone-like activity Decomposition 'of this strych- (asmeasured by the granuloma inhibition test) than eitherd-ll-keto-progesterone or cortisone. The fact thatdl-llketo-progesterone possess greater cortisone-activity than d-ll-keto-progesterone is particularly unobvious in view of the fact thatthe corresponding l-isomer is substantially inactive.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

' Example 1 To a solution of 24 g. of 1-ethoxyethinyl-2-methallyl- 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene-1-ol-4-one (M. P. 133- 134 C.) in 160 ml.of tetrahydrofuran was added 10 ml, of 10% aqueous sulfuric acid. Theresulting mixture was maintained at a temperature within the range of 27C. to 29 C. for a period of about three and one-half hours. At the endof this time, an excess of a saturated aqueous solution of sodiumbicarbonate was added to the reaction mixture, and the tetrahydrofuranwas evaporated from the aqueous mixture under reduced pressure. The oilwhich separated Was extracted into ether; the ether extract was washedonce with water, dried over sodium sulfate, and the ether wasevaporated. The residual oily material was dissolved in ether andchromatographed on acid-washed alumina. The adsorbate was eluted withmixtures of ether and petroleum ether; upon evaporation of the 8:2petroleum ether-ether eluate there was obtained 1 carboethoxymethylene 2methallyl-2,4b-dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one; uponevaporation of the 7:3 petroleum ether-ether eluate there was obtainedl-carboethoxymethyl 2 methallyl 2,4b dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a.- dodecahydrophenanthrene 1 ol 4 one havingan M. P. of 99-10l C.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 ethoxyethinyl- 2 methallyl 24bdimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-ol-4-one having an M. P. of 133-134 C., therewas obtainedthe stereoisomer of l-carboethoxymthyl-Z-methallyl 2,4bdimethyl 7 ethylenedioxy f 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1- ol-4-one having an M. P. of 99-101 C. and thestereoisomer of l-carboethoxymethylene 2 methallyl 2,4bdimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenel-onehaving an M. P. of 133- 134 C. and 151-152 C. (dimorphic).

By using a stereochemical modification of the above 1 ethoxyethinyl 2methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-ol-4-one starting material having an M. P. of131-132" C. there was obtained the stereoisomer *of l-carboethoxymethyl2 methallyl 2,4b dimethyl- 7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-ol-4-one having an M. P. of 146 C.

and the stereoisomer of 1 carboethoxymethylene 2 methallyl 2,4b dimethyl7 ethylenedioxy l,'2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene4,- one having an M. P. of 94-96 C.

Example 2 boxymethylene 2 methallyl 2,4b dimethyl 7-ethyl-' enedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one separated asan oil, and approximately 50 ml. of water was added to dissolve thesalt. The aqueous mixture was extracted once with ether, and thenacidified with excess sodium dihydrogen phosphate, Th acidified mixturewas then extracted with chloroform, and the chloroform extract was driedover sodium sulfate, filtered and evaporated to dryness under reducedpressure at a bath temperature which did not exceed about 40 C. Theresidual crystalline material was washed with ether and recrystallizedfrom ethyl acetate to give substantially pure l-carboxymethylene 2methallyl-2,4bdimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1-carboethoxymethylene-2-methallyl2,4b dimethyl- 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one having an M. P. of 133-134 C.; 151.2 C.,there was obtained the stereoisomer of 1 carboxymethylene 2 methallyl2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one having an M. P. of 223-225 C.

When the stereoisomer of 1-carboethoxymthylene-Z- methallyl 2,4bdimethyl '7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,l0adodecahydrophenanthrene 4 one having an M. P. of 94-96 C. was used asstarting material and the saponification conducted as described in thefirst paragraph of the present example except that the potassiumhydroxide was omitted from the saponification mixture, there wasobtained the stereoisomer of l-carboxymethylene-Z methallyl 2,4bdimethyl-lethylene- 4 dioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10adodecahydrophenanthrene-4-one having an M. P. of 203-205 C.

A solution containing about 50 mg. of l-carboxymethylene 2 methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one and about 15 mg. of p-toluene sulfonicacid in about 3 ml. of acetone was heated under reflux for a period ofapproximately twenty minutes. The acetone reaction mixture was dilutedwith Water and the resulting aqueous mixture was extracted. withchloroform. The chloroform extract was dried and evaporated to drynessto give 1-carboxymethylene-2methallyl-2,4b-dimethyl-k,

1 5 2,3,4,4a,4b,5,6,7,9,10,1021 dodecahydrophenanthrene 4 7-dione.

Example 3 A solution of 100 mg. of l-carboXymethylene-2-methallyl 2,4bdimethyl 7 ethylenedioxy l,2,3,4,4a,4b, 5,6,7,8,l0,ladodecahydrophenanthrene 4 one was suspended in 5 ml. of water. One grameof sodium borohydride was added cautiously until the initial reactionwas completed. After all of the reducing agent had dissolved, themixture was heated at 100 C. for three hours. The reaction mixture wascooled, acidified with sodium dihydrogen phosphate, and the acidifiedmixture extracted with chloroform. The chloform extract was washed withwater, dried over anhydrous sodium sulfate, and filtered, and thechloroform was evaporated from the filtered solution in vacuo at a bathtemperature of less than about 40 C. The residual oil was crystallizedfrom ether, and recrystallized from ethyl acetate to give substantiallypure l-carboxymethylene 2 methallyl-2,4bdimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol.

In accordance with the foregoing procedure and utilizing as startingmaterial the stcreoisomer of l-carboxymethylen Z-methallyl 2,4b-dimethyl7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene 4-one having an M. P. of 223-"25 C. there was obtained the stereoisomer ofl-carboxymethylene-2-methallyl-2,4bdimethyl 7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol having an M.P. of 211- 214 C.

Upon heating,under reflux, a solution of 50 mg. of l-carboxyrnethyleneZ-methallyl 2,4b-dimethyl 7- ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrcnel-ol and mg. ofp-toluene sulfonic acid in 3 ml. of acetone for a period of aboutminutes, there is obtained l-carboxymethylene-2-methallyl-2,4b-dimethyl.l,2,3,4,4a,4b,5,6,7,9,l0,1021-dodecahydrophenanthrene-4-ol-7-one.

' Example 4 A suspension of 5 g. of 1-carboxymethylene-Z-methal: lyl2,4b-dirnethyl 7-ethylenedioxy l,2,3,4,4a,4b,5.6,7,8,10,10a-dodecahydrophenanthrene-4-0ne in 20 ml. of tetrahydrofuran and200 ml. of liquid ammonia was stirred at a temperature of 40 C. whilepea-sizedportions of lithium were added at intervals and at a ratesutficient to maintain an excess of the alkali metal. The liquid ammoniareaction mixture was stirred at a temperature of about 40 C. for a totaltime of about two hours during which the addition of the lithium wascontinued; a total of about 500 mg. of lithium was used. The excessammonia was evaporated from the reaction mixture at room temperature,about 200 ml. of benzene was added, and ethyl acetate was then addedcautiously to destroy the excess lithium. One hundred and fiftymilliliters of water was added to the mixture and the benzene layer wasdiscarded. The alkaline aqueous layer was acidified with excess sodiumdihydrogen phosphate and the acidified aqueous mixture extracted withchloroform. The chloroform extract was washed with water, dried overanhydrous sodium sulfate, filtered, and the chloroform evaporated fromthe filtered solution under reduced pressure. The residual oil wascovered with 50 ml. of ether and the mixture heated under reflux forabout fifteen minutes. The crystalline precipitate which formed wasrecovered by cooling the ethereal mixture and filtering. Thiscrystalline material was fractionally crystallized from acetonitrile togive 1-carboxymethyl-2-methallyl- 2,4b-dimethyl 'l-ethylencdioxy1,2,3,4,4a,4b,5,6,7,8,10, l0a-dodecahydrophcnanthrene-4-one, whichcrystallized first, and l-carboxymethyl- Z-methallyl- 2,4b-dimethyl- 7-ethylenedioxy 1,2,3 ,4,4a,4-b,5,6,7,8, l 0, 1 Oa-dodecahydrophcnanthrene-4-ol (the more soluble compound).

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer. of

16 l-carboxymethylene Z-methallyl 2,4b-dirnethyl 7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 223225? C., there were obtained the stereoisomer ofl-carboxymethyl-Z- methallyl 2,4b-dimethyl 7-ethylenedioxyl,2,3,4,4a,4b,

5,618,10,10a-dodecahydrophenanthrcne-4-one having an M. P. of 20l203 C.,and two stereoisorners of l-carboxymethyl Z-methallyl2,4b-dime1hyl-7-ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene- 4-ol, one of which has-an M. P. of 226-228 C.and the other an M. P. of 234-235 C.

When the stereoisorner of l-carboxymethyl-Z-methallyl- 2,4b-dimethyl7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M. P. of 203-205 C. was usedas starting material there were obtained two stereoisomers ofl-carboxymethyl-2-rnethallyl 2,4b-dimetl1yl 7-ethylenedioxyl,2,3,4,4a,4b,5,6,7, 8,l0,10a-dodecahydrophenanthrene-4-ol one of whichhas an M. P. of 225-257 C. and the other an M. P. of 216- 220 C.

When l-carboxymethylene- 2-rnethallyl- 2,4b-dirnethyl- 7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodehydrophenanthrenel-ol was untilized asstarting material in the foregoing procedure, the product obtained wasl-carboxymethyl Z-methaliyl 2,4b-dimethyl 7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophenanthrene- 4-01.

A solution containing about 50 mg. of l-carboxymethyl- 2-methallyl2,4b-dimethyl 7-ethylenedioxy l,2,3,4',4a, 4b,5,6,7,8,10,10adodecahydrophenanthrene 4 01 and about 15 mg. of p-toluene sulfonic acidin about 3 ml. of acetone was heated under reflux for a period of abouttwenty minutes. The acetone reaction mixture was diluted with Water andthe resulting aqueous mixture extracted with chloroform. The chloroformextract was dried and evaporated to dryness to give l-carboxymethyl-Z-methallyl 2,4b-dimethyll,2,3,4,4a,4b,5,6,7,9,l0,10adodecahydrophenanthrene-4-ol-7-one. When thestereoisomer of l-carboxymethyl Z-methallyl 2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1021dodecahydrophenanthrene-4-ol having an P. of 255-257 C. was hydrolyzedin accordance with the foregoing procedure there was obtained thestereoisomer of l-carboxymethyl Z-methallyl 2,4b-dimethyll,2,3,4,4a,4b,5,6,7, 9,10,10a-dodecahydrophenanthrene-4-ol-7-one havingan M. P. of 215-217 0.; when the stereoisomer of l-carboxyrnethylZ-rnethallyl 2.4b-diniethyl 7-ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,l0,1021 dodecahydrophenanthrene-4-ol having an M.P. of 2l6220 C. was similarly hydrolyzed there was obtained thestereoisomer of l-carboxymethyl Z-methallyl 2,4b-dimethyl l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol-7-one having an M. P. of 192C.

When l-carboxymethyl Z-methallyl 2,4b-dimethyl- 7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophenanthrenel-one is similarlyhydrolyzed using an acetone solution of p-toluene sulfonic acid, thereis obtained l-carboxymethyl-2-1nethallyl-2,4b-dimethyl-1,2,3,4,4a,4b,5,6,7,9,l0,10a-dodecahydrophenanthrene'4,7-dione.

Example 5 One and two-tenths gram of sodium metal was added to 20 ml. ofrefluxing ethyl alcohol. followed immediately by one-half gram ofl-carboxymcthylene2-methallyl 2,4b-dimethyl 7-ethylenedioxy1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrenel-one. Theresulting mixture was stirred vigorously for a period of about fifteenminutes. The reaction mixture was evaporated to onehalf volume in vacuo,and the concentrated solution was diluted with water. The aqueoussolution was extracted with chloroform, and this extract, after beingdried, was evaporated to dryness in vacuo. The residual crystallinematerial was fractionally crystallized from scetonitrile to givesubstantially pure l-carboxymethyl-2-inethallyl-2,4b-

17 dimethyl 7-.ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-

.dodecahydrophenanthrene-4-ol.

One part of 1-carboxymethylene-Z-methallyl-2,4b-dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-

dodecahydrophenanthrene-4-one (M. P. 203205 C.) was reacted with about2.4 parts of sodium metal utilizing the same procedure as that describedin Example 5 hereinabove except that n-butanol was used for thereduction medium in place of ethyl alcohol. The reaction mixture wasworked up as in Example 5 to give substantially pure1-carboxymethyl-2-methally1,2,4b-dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol (M. P. 255-257C.).

Example 7 A mixture of one part of1-carboxymethylene-2-methallyl-2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8, 10,1Oa-dodecahydrophenanthrene-4-0ne (M. P.203-205 C.), about 4 parts of potassium metal, and about 40 ml. ofn-butanol was stirred at the reflux temperature of the solvent for aperiod of about fifteen minutes. The reaction mixture was worked up asin Example 5 hereinabove to give substantially pure1-carboxymethyl-Z-methallyl- 2,4b-dimethyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,l0, a-dodecahydrophenanthrene-4-01(M. P. 255257 (3.).

Example 8 A solution of 2.75 g. of 1-carboxymethyl-Z-methallyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol was treated with an excess ofdiazomethane in ether. After standing overnight at room temperature, thesolvents were removed by evaporation The residual oil was crystallizedfrom ether, and the crystalline material thus obtained recrystallizedfrom a mixture of ethyl acetate, ether, and petroleum ether to givesubstantially pure l-carbomethoxymethyl-Z-methallyl 2,4b dimethyl 7ethylenedioxy- 1,2 ,3 ,4,4a,4b,5,6.,7,8,10,10a dodecahydrophenanthrene-4-.01.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of1-carboxymethyI-Z-methallyl-2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a didecahydrophenanthrene-4-ol having an M.P. of 226228 C., there was obtained the stereoisomer ofcarbomethoxymethyl-Z- methallyl-2,4b-dimethyl-7-ethylenedioxyl,2,3,4,4a,4b,5, 6,7,8,10,10a-dodecahydrophenanthrene 4 01 having an M.P. of 226-228 C., there was obtained the stereoisomer ofcarbomethoxymethyl-Z-methallyl-2,4b-dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol having an M.P. of 138139 C.

When the stereoisomer ofl-carboxymethyl-Z-methallyl-2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene-4-ol having an M.P. of 255257 C. was used as starting material there was obtained thestereoisomer of l carbomethoxymethyl 2- metha1lyl-2,4b-dimethyl 7ethylenedioxy-1,2,3,4,4a,4b, 5,6,7,8,10,10a dodecahydrophenanthrene-4-olhaving an M. P. of 157-158 C.

When the stereoisomer of l-carboxymethyl-Z-methallyl- 2,4b 7 dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol-having an M. P. of 216220 C. wasused as starting material there was obtained the stereoisomer of1-carbomethoxymethyl-2-methaIIykZAb-dimethyl 7ethylenedioxy-1,2,3-,4,4a,4b,5,6,7,

18 8,10,10a-dodecahydrophenanthrene-4-01 having an M. P. of 8385 C.

A solution containing about 50 mg. ofl-carbomethoxymethyl-Z-methallyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene- 4 01 and about 15 mg.of p-toluene sulfonic acid in about 3 ml. of acetone was heated underreflux for a period of about twenty minutes. The acetone reactionmixture was diluted with water and the resulting aqueous mixtureextracted with chloroform. The chloroform extract was dried andevaporated to dryness to give l-carbomethoxymethyl 2methallyl-2,4b-dimethyl-1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4-ol-7-one. When the stereoisomer of1-carbomethoxymethyl-Z-methallyl-2,4bdimethyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,,l0adodecahydrophenanthrene-4-olhaving an M. P. of.l37 138 C. was used as starting material, there wasobtained the stereoisomer of 1-carbomethoxymethyl-Znnethallyl-2,4b-dimethyl-l,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4-ol-7-one having an M. P. of 13'3 -134 C.

Example 9 A suspension of 4.15 g.ofl-carboxymethyl-Z-methallyl-2,4b-di1nethyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,10,lOa-dodecahydrophenanthrenel-oland 8 g. of anhydrous potassium carbonate in 50 ml. of dry acetonecontaining 8 ml. of methyl iodide was stirred, in a looselystopperedflask, at room temperature for a period of about fifteen hours. Thereaction solution was filtered thereby removing the precipitatedpotassium iodide and excess potassium carbonate. The acetone wasevaporated from the'filtered solution in vacuo, and the residual oil wasdissolved in ether; the ethereal solution was washed twice with 10rnL-portions of water, dried over anhydrous sodium sulfate, and thesolvents evaporated. The residual oil was crystallized from ether anddried to give substantially pure 1 carbomethoxymethyl 2methallyl-2,4bdimethyl 7ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol.

In accordance with the foregoing experimental procedure and utilizingthe stereoisomer of l-carboxyrnethyl-Z- -methallyl-2,4b-dimethyl 7ethylenedioxy- 1,2,3,4,4a,4b,

5,6,7,8,10,10a dodecahydrophenanthrene-4-ol having an M. P. of 216-220C. as starting material, there was obtained the stereoisomer of1-carbomethoxymethyl-2-methallyl-2,4b-dimethyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene-4-olhaving an M. P. of 83-.-85 C.

Example 10 A solution of 350 mg. of 1-carbomethoxymethyl-2-methallyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol in 3.5 ml. of pyridine wasadded to the complex formed by adding 350 mg. of chromium trioxide to3.5 ml. of pyridine. The resulting mixture was shaken, and allowed tostand at room temperature in a closed vessel for a period of aboutfifteen hours. The reaction mixture was diluted with about 30 m1. ofwater, and the aqueous solution Was extracted with three 50 ml.-portionsof ether. The ethereal extracts were combined, washed twice with water,dried over anhydrous sodium sulfate, and the solvent evaporated. Theresidual oil was crystallized twice from ether to give substantiallypure l-carbomethoxymethyl-Z- methallyl-2,4b-dimethyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,1Oa-do-decahydrophenanthrenel-one.

In accordance with the foregoing experimental pro-.. cedure andutilizing as starting material the stereoisomer of 1 carbomethoxymethyl2 methallyl 2,4b dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-o1 having an M. P.of l38- 139 C. there was obtained the stereoisomer ofl-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M.P. of -127 C.; when the stereoisomer of 1-carbomethoxymethyl-Z-meth- 19allyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,-

5,6,7,8,10,10a dodecahydrophenanthrene 4 ol having an M. P. of 157-158C. was used as starting material there was obtained the stereoisomer ofl-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenan- I threne-4-one having anM. P. of 140141 C.; when the stereoisomer of1-carbomethoxymethyl-Z-methallyl-2,4bdimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-

. dodccahydrophenanthrene-4 01 having an M. P. of 83-85 C. was used asstarting material there was obtained the stereoisomer of1-carbomethoxymethyl-2-methallyI-2,4bdimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5.6,7,8,10,la-

dodecahydrophenanthrene-4-one having an M. P. of 142 When thestereoisomer of 1-carboxymethyl-Z-methallyl- 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,

: 10,10a-dodecahydrophenanthrene-4-ol having an M. P. of

234-235 C. was reacted with diazomethane in ether in accordance with theprocedure described in Example 8 hereinabove, and the resultingstereoisomer of 1-carbo-' methoxymethyl 2 methallyl 2,4b dimethyl 7ethyl enedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-olreacted with chromium trioxide-pyridine complex in accordance with theprocedure described in To a solution of 378 mg. ofl-carbomethoxymethyl-2- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodccahydrophenanthrene-4-one in 3 ml. of dry etherand 0.5 ml. of dry benzene was added 254 mg. of osmium tetroxide. Theresulting solution began to deposit in a few minutes a brown-blackprecipitate which can be recovered by filtration and dried to give theosmate ester of 1carbomethoxymethyl-2- (beta, gamma dihydroxyisobutyl)2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one. Instead of isolating the osmate ester,the reaction mixture was allowed to stand at room temperature for aperiod of one hour, and 18 ml. of ethanol was then added to the reactionmixture. A solution of 0.8 g. of anhydrous sodium sulfite in 9 ml. ofwater was added to the alcoholic reaction mixture, the resulting mixturewas vigorously agitated for a period of about threeminutes, and theprecipitated osmium oxide removed by filtration. The filtered reactionsolution was cautiously acidified with dilute acetic acid to a pH ofabout 6, and the mildly acid aqueous solution was evaporated underreduced pressure to an oil. Water was added to the oil, and the aqueousmixture was extracted with ether. The ether extract was washed withwater, dried over anhydrous sodium sulfate, and the ether evaporated.The residual crystalline material was crystallized from ethyl acetate togive 1-carbomethoxymethyl-2-(beta, gamma dihydroxyisobutyl) 2,4b dldimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 carbomethoxymethyl 2 methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a

dodecahydrophenanthrene-4-one having an M. P. of 125- 127 C., there wasobtained the stereoisomer of 1- carbomethoxymethyl 2 (beta,garnmadihydroxy isobutyl) 2,4b dimethyl 7 ethylenedioxy l,2,3,4, ,7,8,10,1Oadodecahydrophenanthrcne 4 one having an M. P. of 172174 C.; when thestereoisomer of l carbomethoxymethyl 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenel-onehaving an M. P. of 140-141" C. was used as starting material, there wasobtained the stereoisomer ofl-carbomethoxymethyl-Z-(beta,gamma-dihydroxyisobutyl) 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4-onehaving an M. P. of 142-155 C.; when the stereoisomer of 1carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7, 8,10,10a dodecahydrophenanthrene 4 one having an M.P. of 142146 C. was used as starting material,

' there was obtained the stereoisomer of l-carbomethoxymethyl 2(beta,garnma dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenel-one having an M.P. of

2,4b dimethyl l,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4,7-dione. Example 12 To a solution of 400 mg.of l-carbomethoxymethyl-Z- (beta,garnma dihydroxyisobutyl) 2,4b dimethyl7- ethylendioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one in 4 ml. of ethanol was added 1 ml. ofpyridine and a solution of 350 mg. of periodic acid in 2 ml. of water.The resulting mixture was allowed to stand for a period of about sixminutes at the end of which time the exothermic reaction which occurredwas substantially complete. The reaction mixture was diluted with 20 ml.of water, and the aqueous mixture extracted with ether. The etherextract was washed with 5 ml. of water, dried over sodium sulfate,filtered and the ether evaporated. The residual oil was crystallizedfrom petroleum ether to give substantially pure l-carbomethoxymethyl- 2acetonyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,-4,4a,4b,5,6,7,8,10,10a-dodecahvdrophenanthreneA-one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 carbomethoxymethyl 2(beta,garnma dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,-4a,5,6,7,8,10,10a dodecahydrophenanthrene 4 one having an M. P. of172-174" C., there was obtained the stereoismer of 1 carbomethoxymethyl2 acetonyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,-8,10,10a-dodecahydrophenanthrene-4-one which crystallized from ether ina crystal form having an M. P. of 108-109 C. and which crystallized fromethyl acetatepetroleum ether in a crystal form having an M. P. of C.;when the stereoisomer of l-carbornethoxymethyl- 2 (beta,garnmadihydroxyisobutyl) 2,4b dimethyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M.P. of 142455 C. was used at starting material, there was obtained thesteroisomer of 1-carbomethoxymethyl-2-acetonyl-2,4b-dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthreneA-onehaving an M. P. of 132- 134 0; when the stereoisomer ofl-carboxymethoxymethyl 2 (beta,garnma dihydroxyisobutyl) 2,4b-dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-onehaving an M. P. of 143- 147 C. was used as starting material, there wasobtained sodium methoxide.

I 21 the stereoisomer of 1-carbomethoxymethyl-Z-acetonyl- 2,4b dimethyl7 ethlenedioxy 1,2,3,4,4a,4b,5,6,7,8,-10,10a-dodecahydrophenanthrene-4-one having an M. P. of 144 C.

Upon heating together, under reflux, l-carbomethoxymethyl 2 acetonyl2,4b dimethyl 7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene- 4-0ne and acetone solution of p-toluenesulfonic acid, there is obtained1-carbomethoxymethyl-2-acetonyl-2,4bdimethyl l,2,3,4,4a',4b,5,6,7,8,10,10a dodecahydrophenanthrene-4,7-dione.

' Example 13 One gram of 1-carbomethoxymethyl-2-methallyl-2-4bdimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-onewas dissolved in 100 ml. of methanol. The resulting solution was cooledto a temperature of about -80 C. and a stream of ozonized oxygencontaining one equivalent of ozone was passed, over a two-minute period,through the cold solution. The reaction mixture was warmed to atemperature of about C., and 10 ml. of water was added to the mixturefollowed by five grams of zinc and 5 ml. of acetic acid. The resultingmixture was stirred for a period of about thirty minutes. Water andsolid sodium carbonate were then added, the mixture was filtered, andthe solvents were evaporated from the filtered solution in vacuo whilemaintaining the temperature of the solution below about C. The residualmaterial was extracted with ether and ether solution chromatographed onacid-washed alumina, Upon evaporation of the ether-petroleum ethereluate there was obtained 1-carbomethoxymethyl-Z-acetonyl-2,- 4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,-10,10a-dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 carbomethoxymethyl 2 methallyl2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one having an M.P. of 125- 127 C., there was obtained the stereoisomer ofl-carbomethoxymethyl 2 acetonyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M.P. of 108-109 C. when crystallized from ether.

Example 14 A solution of 506 mg. of l-carbomethoxymethyl-Z- acetonyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,- 4b,5,6,7,8,10,10a-dodecahydrophenanthrenet one in benzene was distilled atroom temperature until the volume of the solution was about 10 ml. Thisprocedure assured a dry solution. This dry solution was added to solid(The solid sodium methoxide was prepared by removing the excess methanolfrom 2.4 ml. of a 1 molar methanol solution of sodium methoxide bybaking at 150 C. for thirty minutes in vacuo.) The mixture of thebenzene solution of the hydrophenanthrene compound and the solid sodiummethoxide was allowed to stand at room temperature for a period of abouttwenty minutes, at the end of which time a fluocculent solidprecipitated from the benzene solution. The resulting mixture wasstirred at room temperature for a period of about fifteen hours. Amixture of cold water (0 C.) and ether was added tothe reaction productand the resulting mixture was vigorously agitated. The aqueous phase wasquickly separated and immediately acidified with an excess of an aqueoussoltuion of sodium dihydrogen phosphate. The acidified aqueous solutionwas extracted with choloroform, and the organic extract was dried overanhydrous sodium sulfate, filtered, and the chloroform evaporated. Theresidual crystalline material was recrystallized from ethylacetate-ether, and from ethanol, to give A-3-ethylenedioxy-11,16,2O-triketo-pregnene.

In accordance with the foregoing experimental procedure andutilizingasstarting material the stereoismer of 1 carbomethoxymethyl 2 acetonyl2,4b dimethylcarbonate solution.

22 7 ethylenedioxy 1-,2,3 ,4,4a,4b',5,6,7,8,10,10adodecahydrophenanthrene-4-one having an M. P. of 132-134" C., there wasobtained the stereoisomer of A-3-ethylenedioxy-l1,16,20-triketo-pregnene having an M. P. of 154- 156C.; when the stereiosomer of l-carbomethoxymethyl 2 acetonyl 2,4bdimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene- 4one having, when crystallized from ether, anM. P. of 108-109 C., there was obtained the stereoisomer of A-3-ethylenedioxy-11,16,20-triketo-pregnene having an M. P. of 226-229"C.; when the stereoisomer of l-carbomethoxymethyl 2 acetonyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro-.phenanthrene-4-one, having an M. P. of 144 C. was used as startingmaterial, there was obtained the stereoisomer of A-3-ethylenedioxy-11,16,20-triketopregnene having an M. P. of 213-215 C.

Upon heating together, under reflux, A-3-ethylenedioxy-l1-16,20-triketo-pregnene and an acetone solution ofp-toluene sulfonic acid (substantially in accordance with the proceduredescribed in Example 1 hereabove), there was obtained A-3,11,16,20-tetraketo-pregnene; when the stereoisomer of A-3-ethylenedioxy-11,16,20-triketopregnene having an M. P. of 154-156 C.is used as starting material in this procedure, there was obtained thestereoisomer of A -3,11;16,20-tetraketo-pregnene having an M. P. of187-189 C.

Example 15 To a solution of 295 mg. of A -3-ethylenedioxy-11,16-20-triketo-pregnene in 3.7 ml. of pyridine was added 370 mg. ofp-toluenesulfonyl chloride. The resulting mixture was allowed to standat room temperature for about twenty-two hours. At the end of thisperiod 2.3 ml. of saturated aqueous sodium bicarbonate solution wereadded to the cooled reaction mixture, thereby neutralizing the pyridinehydrochloride formed by the reaction as well as the excessp-toluenesulfonyl chloride. The aqueous pyridine mixture was agitated atroom temperature for a period of about fifteen minutes during which timea crystalline product precipitated. Benzene was added tothe reactionmixture, the mixture was poured onto ice, and dilute aqueoushydrochloric acid was added until the mixture was just'acid. The organiclayer was rapidly separated, washed with water, and with aqueous sodiumbi- The washed organic layer was dried over sodium sulfate, andevaporated to dryness in vacuo.

The residual material was recrystallized from benzenepetroleumether-ether and then chromatographed on acidwashed alumina. The materialobtained from the 1:1 petroleum ether-ether eluate was recrystallizedfrom benzene-ether to give substantially pure A-3-ethylenedioxyl6-p-toluenesulfonoxy-1 1,20-diketo-pregnadiene.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of A-3-ethylenedioxy-l1,16,20-triketo-pregnene having an M. P. of l54-156C., there was obtained the stereoisomer of A-3-ethylenedioxy-16-p-toluenesulfonoxy-l 1,20-diketo-pregnadiene havingan M. P. of 199-201" C.; when the stereoisomer of A-3-ethylenedioxy-1l,16,20-triketo pregnen'e having an M. P. of 226-229C. was used as starting material, there was obtained the stereoisomer ofA -3-ethylenedioxy-16-p-toluenesulfonoxy-1 1,20-diketo pregnadienehaving an M. P. of 189-190 C.; when the stereoisomer of A-3-ethylenedioxy-l1,16,20-triketo-pregnene having an M. P. of 213-215 C.was used as starting material, there was obtained the stereoisomer of A-3-ethylenedioxy-16-p-toluenesulfonoxy- 1 1,20-diketo pregnadiene havingan M. P. of 198-200 C.

Upon heating together, under reflux, A -3-ethylenedioxy-l6-p-toluenesulfonoxy 11,20 diketo pregnadiene and an acetonesolution of p-toluenesulfonic acid, there is obtained A-16-p-toluenesulfonoxy-3-,1 l,20-triketo-preg'- nadiene.

23 Example 16 To a solutionof 52 mg. of A-3-ethylencdioxy-16-ptoluenesulfonoxy-l1,20-diketo-pregnadiene in ml. ofbenzene was added 2 g. of palladium catalyst (5% Pd on BaCO and themixture was shaken at room temperature in contact with hydrogen under apressure of about forty. pounds per square inch. After about two hours,

an additional 0.8 g. of catalyst was added and, after four morehours,another 0.8 g. of catalyst was added to the hydrogenation mixture. Theresulting mixture was shaken for an additional fifteen hour period atroom temperature in contact with hydrogen at a pressure of forty pounds.per. square inch. The reatcion mixture was filtered thereby removingthe catalyst and the benzene was evaporated from the filtered soltuionin vacuo. The residual material was treated with ether and thecrystalline product thus obtained was recrystallized fromether-petroleum ether-ether to give substantially pure A-3-ethylenedioxy-l1,20-diketo-pregnene.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of A-3-ethylenedioxy-16-p-toluenesulfonoxy-l1,20-diketopregnadiene having anM. P. of 199-201" C. (which was prepared using the stereoisomer of A-3-ethylenedioxy- --11,16,20-triketo-pregnene ofM. P. 154-156 C.), therewas obtained the stereoisomer of A -3 ethylenedioxy-l 1,20-diketo-pregnene having an M. P. of 181182.5 C.; when the stereoisomer ofA -3-ethylenedioxy-lo-p-toluenesulfonoxy-l1,20-diketo-pregnadiene havingan M. P. of 189- 190 C. was used as starting material, there wasobtained the stereoisomer of A -3-ethylenedioxy-l1,20-diketo-pregnenehaving an M. P. of 142145 C.; when the stereoisomer of A-3-ethylenedioxy-16-p-toluenesulfonoxy- 11,20-diketo-pregnene of M. P.171-172: c.

Example 17 To a solution of 20 mg. of A -3-ethy1enedioxy-11,20-diketo-pregnene in 1 ml. of tetrahydrofuran was added 0.5 ml. of 3 Naqueous perchloric acid solution. The reaction mixture was allowed tostand at room temperature for a period of approximately three andone-half hours. The solvents were evaporated from the reaction mixturein vacuo. and the residual material was extracted a with chloroform. Thechloroform extract was dried over sodium sulfate, and the solventevaporated from the dry chloroform extract in vacuo. The residualmaterial was recrystallized from ether of give A-3,11,20-triketo-pregnene.

In accordance with the foregoing experimental procedure and utilizingthe racemate of A -3-ethylen'edioxy- 11,20-diketo-pregnene having an M.P. of 181-1825 C. as starting material, there was obtained the racemateof A -3,l1,20-diketo-pregnene having an M. P. of 175.5- 176.5 C.; whenthe racemate of A -3-ethylenedioxyl1,20- diketo-pregnene having an M. P.of l42l45 C. was used as starting material, there was obtained theracemate of 'A*-3,l1,20-triketo-pregnen'e having an M. P. of l53158 C.;when the racemate of A -3-ethylenedioxy-11,20-diketopregnene having anM. P. of 171-172 C. was used as starting material, there was obtainedthe racemate of A -3,11,20-triketo-pregnene having an M. P. of 153 C.and 168' C. (dimorphic).

The racemate of A -3,'11,20-triket0-pregnene having an M. P. of175.$-176.5' C. possesses the stereoisomeric configurationcharacteristic of the naturally occurring steroid hormones such asprogesterone; we refer to this racemate (M. P. 175.5-176.5 C.) asdl-ll-keto-progesterone.

Example 18 To a solution of 222 mg. of l-ethoxyethinyl-Z-methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,

4b,5,6,7,8,10,10a dodecahydrophenanthrene 1,4 diol (M. P. 108-111 C.) in2 ml. of tetrahydrofuran was added 0.008 ml. of concentrated sulfuricacid. After three minutes at room temperature, an excess of sodiumbicarbonate solution was added to the reaction mixture and thetetrahydrofuran was evaporated. The organic material which separated wasextracted into ether; the ether extract was washed once with water,dried over magnesium sulfate and the ether was evaporated. The residualoily material was dissolved in benzene and chromatographed onacid-washed alumina. The adsorbate was eluted with mixtures of ether andpetroleum ether; upon evaporation of the 2:8 ether-petroleum ethereluate there was obtained l-carbethoxymethylene- 2 methallyl 2,4bdimethyl 7 ethylenedioxy 1,2, 3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4'01 whichmelted at -120 C. after purificationby recrystallization from ether-petroleum ether.

Example 19 A suspension of 60 mg. of l-carbethoxymethylene- 2 methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,

.4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01 (M. P. 105l20 C.)in 5 ml. of methanol and 5 ml. of

water containing 0. 5 g. of potassium carbonate and 1 ml. of 1 Npotassium hydroxide was heated under reflux for three hours. Themethanol was evaporated under reduced pressure and the aqueous residuewas diluted with water and extracted with ether to remove any neutralmaterial. TIhe aqueous solution was acidified with excess sodiumdihydrogen phosphate and the acidified mixture was extracted withchloroform. After drying over magnesium sulfate, the chloroform extractwas filtered and evaporated to dryness under reduced pres sure. Theresidual material was crystallized from benzene-petroleum ether to givesubstantially pure l-carboxymethylene 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-olmelting at 174180 C.

Treatment of the 1 carboxymethylene 2 methallyl- 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,lOa-dodecahydrophenanthrene-4-olwith a slight excess of diazomethane in ether solution gavel-carbomethoxymethylene 2 methallyl 2,4b dimethyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol, M. P. 134135C.

Oxidation of the l-carbomethoxymethylene 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4a,4b, 5,6,7,8,l0,10a dodecahydrophenanthrene 4 01(M. P. 134-135 C.) with chromic anhydride and pyridine gave astereoisomer of l-carbomethoxymethylene-Z-methallyl- 2,4b dimethyl 7ethylenedioxy l,2,3,4,4a,4b,5,6,7, 8,10,10a dodecahydrophenanthrene 4one, M. P. 153 C. Example 20 A solution of 229 mg. of1-carboxymethylene-Z-methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b, 5,6,7,8,10,10a dodecahydrophenanthrene 4 01 in 5 ml. ofether was added to a solution of 40 mg. of lithium in 10 ml. of liquidammonia at 78 C. The liquid ammonia reaction mixture was allowed to warmto -40 C. with stirring. After twenty minutes the blue lithium color wasdischarged. An additional 40 mg. of lithium was added and the mixturewas stirred at 40 C. for an additional hour. The excess ammonia wasevaporated. from the reaction mixture. at room temperature and ml. ofether was added. Ethyl acetate was then added cautiously to destroy theexcess lithium. Water was added to the mixture and the ether layer wasdiscarded. The alkaline aqueous layer was acidified with excess sodiumdihydrogen phosphate and the acidic product was extracted withchloroform. The chloroform extract was washed with water, dried overmagnesium sulfate, filtered, and the chloroform evaporated under reducedpressure. Crystallization of the residue from benzene gave substantiallypure l-carboxymethyl- 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 ol melting at 195-197C.

Oxidation of the l-carboxymethyl-2-methallyl-2,4bdimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-olwith chrornic anhydride and pyridine gave l-carboxymethyl-Z-methallyl-2,4bdimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one.

Treatment of the 1-carboxymethyl-Z-methallyl-Z,4bdimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-olwith a slight excess of diazornethane in ether solution gavel-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a do-decahydrophenanthrene-4-ol, M. P. 14244C.

Example 21 One gram of 1-carboxymethyl-2-methallyl-2,4bdimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-onewas dissolved in 30 ml. of Water containing 1.1 ml. of 4 N aqueoussodium hydroxide and 10 ml. of ethanol. One gram of sodium borohydridewas added, and the solution was allowed to stand at room temperatureovernight. One more gram of sodium borohydride was added, and thesolution was boiled 1 /2 hours. It was poured into ice water, andacidified with excess sodium dihydrogen phosphate. The acid mixture wasextracted twice with chloroform, the combined extracts were evaporated,and the amorphous residue was crystallized from ether. Recrystallizationfrom ethyl acetate and from tetrahydrofuran-petroleum ether afiordedl-carboxymethyl- 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 ol, M. P. 167169 C.

Example 22 To a solution of 20.7 g. of1-ethoxyethinyl-2-allyl-2,4bdimethyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-ol-4-one(M. P. 83.5-85.0 C.) in 165 ml. of absolute tetrahydrofuran was added12.0 ml. of 10% aqueous sulfuric acid. The temperature of the solutionwas maintained at a temperature of 2830 C. for a period of three andone-half hours. After the first 45 minutes had elapsed, there was added0.17 ml. of pyridine, and the reaction mixture Was stirred for theremaining time. The reaction was quenched by the addition of excessaqueous sodium bicarbonate. The organic solvent was distilled off invacuo and the remaining material extracted with ether. The extract waswashed with water, dried over magnesium sulfate, and concentrated todryness. Chromatography of the oily residue over 800 g. of alkalinealumina yielded l-carboethoxymethylene-Z-allyl-2,4bdimethyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4- one, an amorphous solid. Further elutionprovided l-carb0ethoxymethyl-Z-allyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1- ol-4-one, M. P.99-101" C.

In accordance with the above method, and using the I stereoisomer of1-ethoxyethinyl-2-allyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-ol-4-one melting at 159160 C., there wasobtained the stereoisomer of 1-carboethoxymethyl-2- 26 allyl 2,4bdimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,10,10adodecahydrophenanthrenel-ol-4-one, M. P. 101 C. I

7 Example 23 A solution of 175 mg. of 1-carboethoxymethylene-2-' underreduced pressure and the aqueous solution acidified with excess, sodiumdihydrogen phosphate. An ether extraction was made of the solution, andthe extract washed with water, dried over magnesium sulfate, andconcentrated in vacuo. The resulting oil crystallized from petroleumether and was recrystallized from benzene-petroleum ether to give purel-carboxymethylene- 2-allyl-2,4b-dimethyl-7-ethylenedi0xy l,2,3,4,4a,4b,5,6,7, 8,10,l0a-dodecahydrophenanthrene-4-one, having a meltingpoint of 163164 C.

Example 24 A suspension of 14.2 g. of 1-carboxymethylene-2-allyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one (M. P. 163l64 C.) in 225 ml. of waterwas dissolved by adding one molar equivalent of aqueous sodiumhydroxide. To this solution was added 21 g. of sodium borohydride, andthe mixture was allowed to stand overnight. The reaction mixture wasthen heated at C. for one hour, cooled, and acidified 'with sodiumdihydrogen phosphate. Extraction of the equeous solution withchloroform, followed by washing the extract with water, drying overmagnesium sulfate, and concentrating to dryness under reduced pressuregave 1-carboxymethylene-2-allyl-2,4bdimethyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,102.-dodecahydrophenanthrene-4-ol, an amorphous solid.

Example 25 1-carboxymethylene-Z-allyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a L dodecahydrophenanthrene-4-one (15 g. ofamorphous material) was added to one liter of anhydrous ammonia cooledto a temperature of --60 C. followed'by the addition of 15 g. ofmetallic potassium. There was then introduced 50 ml. of anhydrousisopropanol over a period of five minutes. The mixture was stirred untilthe reaction was over as evidenced by the disappearance of the bluecolor characteristic of metallic potassium in liquid ammonia. Theammonia was allowed to evaporate overnight. The remaining solution wasthen concentrated almost to dryness under reduced pressure. Two hundredmilliliters of Water were added followed by addition of a solution of 70g. of sodium dihydrogen phosphate and 50 g. of 85% phosphoric acid in500 ml. of water. The crystalline material thus obtained was filteredand washed thoroughly with water, yielding1-carboxymethyl-Z-allyl-2,4b-dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol, M. P.235.5236.0 C.

Example 26 To a solution of 10.90 g. of l-carboxvmethvl-2-allyl-2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene-4-ol (M. P. 235.5236.0 C.) in one liter ofabsolute tetrahydrofuran was added an excess of diazomethane in ether.After standing overnight at room temperature, the solvents were removedby evaporation, and the residual material crystallized from ethylacetate-petroleum ether to give substantially pure l-carbomethoxymethyl2 allyl-2,4b-dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-4-ol, M. P. 113-115C. Recrystallization of this material from aqueous methanol gave asecond crystalline modification, M. P. -132" C.

and crystallized by addition of water, to give substantially pure1-carbomethoxymethyl 2 allyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene-4-ol.

Example 28 A solution of 9.35 g. of 1-carbomethoxymethyl-2-allyl- 2,4bdimethyl 7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,l0,

10a-dodecahydrophenanthrene-4-ol in 100 ml. of pyridine was added to thecomplex formed by adding 10 g. of

chromium trioxide to 100 ml. of pyridine. After standing at roomtemperature overnight the resulting mixture was diluted with an equalvolume of water. The solution was then extracted with ether, and theextract washed with Water, dried over magnesium sulfate, andconcentrated to about 100 ml. One hundred milliliters of methanol werethen added followed by addition of 500 ml. of water. The material whichcrystallized was filtered and dried to give1-carbomethoxymethyl-2-allyl-2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one crystallized;M. P. 108-109 C.

Example 29 To a solution of 400 mg. of l-carbomethoxymethyl-Z- allyl2,4b-dimethyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in 4 ml. of anhydrous ether wasadded 280 mg. of osmium tetroxide. The resulting mixture was stirred atroom temperature for 45 minutes. To the mixture was added 20 m1. ofethanol and a solution of 1.7 g. of sodium sulfite in 11 ml. of water.The solution was shaken for 20 minutes and then filtered. The filtratewas concentrated to about 10 ml. and extracted with chloroform. Theextract was washed with water, dried overmagnesium sulfate, andconcentrated to dryness in vacuo. Crystallization of the residue frombenzene-petroleum ether gave l-carbornethoxymethyl 2 (beta,gamma-dihydroxypropyl), 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0, 10a dodecahydrophenanthrene 4 one, M. P. 163-164 C. Acidification of the aqueous layer from the chloroform extractionwith excess sodium dihydrogen phosphate and extraction with chloroformfollowed by washing the extract with water, drying over magnesiumsulfate, and concentrating to dryness in vacuo, provided 1carbomethoxymethyl 2 (beta, gamma-dihydroxypropyl) 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a dodecahydrophenanthrene 4one, which after recrystallization from pyridine-petroleum etherdecomposed at 228 C.

Example 30 Two hundred milligrams of 1 carboethoxymethyl 2 methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a, 4b, 5,6,7,8,10,10adodecahydrophenanthrene 1 ol 4 one in ml. of acetone were treated with 5drops of hydrochloric acid and heated under reflux twenty minutes. Theproduct was crystallized from ether to give 1 carboethoxyrnethyl 2methallyl 2,4b dimethyl l,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene 1 ol 4,7 dione M. P. l22-l24 C.

Example 31 Three hundred milligrams of 1 carboethoxymethyl V Theresidual oil was taken up in a small volume of methanol 2 methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,l0,l0adodecahydrophenanthrene 1 ol 4 one were heated in 10 ml. of 2 Npotassium carbonate in 50% aqueous methanol under reflux for sevenhours. The methanol was removed in vacuo and the resulting alkalinesolution was washed with ether. The washed alkaline solution was thenacidified with excess sodium dihydrogen phosphate followed by extractionwith chloroform, drying and concentration to give crystalline 1carboxymethyl 2 methallyl 2,4b dimethyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1 ol 4 one aftercrystallization from ethyl acetate; M. P. 213-215 C. This compound washeated for a short while in acetone and a trace of hydrochloric acid.Dilution with water gave 1 carboxymethyl 2 methallyl 2,4b dimethyl1,2,3,4,4a,5,6, 7,9,10,10a dodecahydrophenanthrene 1 ol 4,7 dione; M. P.205-210" C. (dec.).

Example 32 The stereoisomer of 1 carboethoxymethylene 2 methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 one (M. P. 94-96 C.) was hydrolyzed as inExample 30 to give thestereoisomer of l-carboethoxymethylene 2 methallyl2,4b dimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene 4,7dione; M. P. 111- 112 C.

Example 33 The stereoismer of 1 carboxymethylene 2 meth allyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10adodecahydrophenanthrene 4 one (M. P. 203-205 C.) was treated withdiazomethane in ethyl ether to produce the corresponding stereoisomer ofl carbomethoxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,5,6,7,8,10,10a dodecahydrophenanthrene 4 one; M. P. l52153.5C.

Example 34 Treatment of l carbomethoxymethyl 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,10a dodecahydrophenanthrene 4 01(M. P. 157- 158 C.) with acetyl chloride in pyridine gave 1carbomethoxymethyl 2 methallyl 2,4b dimethyl 4 acetoxy 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene; M. P. 140-141 C.

Treatment of l carbomethoxymethyl 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,10a dodecahydrophenanthrene -'401 (M. P. 83- 85 C.) with acetyl chloride in pyridine gave 1carbomethoxymethyl 2 methallyl 2,4b dimethyl 4 acetoxy 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene; M. P. -126 C.

Treatment of 1 carboxymethylene 2- methallyl 2, 4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, 10a dodecahydrophenanthrene 4 01(M. P. 2l1-2l4 C.) with acetyl chloride in pyridine gave 1carboxymethylene 2 methallyl 2,4b dimethyl 4 acetoxy 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene; M. P. 125-126 C.

Example 35 One quarter milliliter of 10% sulfuric acid was added to asolution of mg. of 1 ethoxyethinyl 2 methallyl 2,4b dimethyl 7ethylenedioxy l,2,3,4,4a,4b,5, 6,7,8,10,10a dodecahydrophenanthrene 1 ol4 one (M. P. of 159-16l C.) in 4 ml. of tetrahydrofuran. After sevenhours at room temperature the reaction mixture was poured into excesssodium bicarbonate solution and the tetrahydrofuran removed in vacuo.The product was extracted with ether and chromatographed over 4.5 g. ofalkaline alumina. With 7:3 petroleum etherzether there was eluted 1carboethoxymethyl 2' methallyl 2,4b dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8, 10,10a dodecahydrophenanthrene 1 ol 4 one.

29 After recrystallization from petroleum ether the crystalline producthad a melting point of 118-119 C.

Example 36 0.9 cc. of ethanedithiol was added to a cooled mixture ofsulfate and .9 g. of l-carbomethoxymethyl-Z-methallyl- 2,4b dimethyl 4,7diketo -'1,2,3,4,4a,4b,5,6,7,9,10, a-dodecahydrophenanthrene. Afterstanding at room temperature for 3 days, the reaction mixture wasextracted with ether. Evaporation of the ethereal extract gave acrystalline residue which, upon recrystallization from ether-petroleumether gave crystalline l-carbomethoxymethyl 2 methallyl 2,4b dimethyl1,2,3, 4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene 4,7-dione-7-ethylenemercaptol.

The parent 7-ketone may be regenerated by treating this product with adilute solution of hydrochloric acid in acetone.

Example 37 A solution of 4 g. of 2-carbomethoxymethyl-Z-methallyl 2,4bdimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4,7-dionein ml. of dioxane was treated with 4 g. of B-mercaptoethanol, followedby the addition of 5 g. of freshly fused zinc chloride and 5 g. ofanhydrous sodium sulfate. The solution was cooled initially in ice andthen allowed to stand at room temperature for 3 days. After dilutionwith water, the reaction mixture was extracted with chloroform. Thechloroform extract was washed with water until neutral, dried and thesolvent evaporated in vacuo. The residual material was recrystallizedfrom ether to give substantially pure1-carbomethoxymethyl-Z-methallyl-2,4b-dimethyl1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4,7 dione 7ethylenehemithioketal. The hemithioketal, prepared according to theforegoing procedure, exhibits substantially no absorption in theultraviolet.

The parent ketone may be reformed by treatment with acetone-hydrochloricacid.

The 1 ethoxyethinyl 2 methallyl 2,4b dimethyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one used asstarting material in Example 1 hereinabove can be prepared from7-keto-4bmethyl 1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-1,4-diol (the preparationof which is describedin Patent No. 2,617,828, issued November 11, 1952), in accordance withthe following procedure:

Into a 5 liter flask equipped with a stirrer, a 1 liter dropping funneland a sidearm with condenser attached in distilling position, wereplaced 38.9 g. (0.155 mole) of 4b methyl 1,2,3,4,4a,5,6,7,9,10,10adodecahydrophenanthrene-1,4-diol-7-one. 40 cc. (0.645 mole) of glycol,2,500 cc. of ethylene dichloride and 0.4 g. (0.002 mole) of p-toluenesulfonic acid. This mixture was set stirring. Enough heat was applied todistill off 3 liters of the azeotrope of the solvent and water, formedas a by-product, during a 3-hour period. During this time an additional1,500 cc. of ethylene dichloride was added to keep the reactants insolution. After 3 hours the reaction mixture was cooled and thoroughlyshaken with 50 cc. of an aqueous 1 Normal potassium bicarbonatesolution. The aqueous carbonate layer was drawn ofl and twice extractedwith ethylene dichloride. All three ethylene dichloride extracts werethen combined, dried over anhydrous magnesium sulfate and concentrated.This concentrate was taken up in 1 liter of acetone and concentrateduntil crystals just began to come out. Filtration of the cold acetonegives the crude crystalline product 4b methyl 7 ethylenedioxy1,2,3,4,4a,4b,5, 6,7,8,l0,10a dodecahydrophenanthrene 1,4 diol which canbe further purified by recrystallization from acetone. The pure productmelts at 189 C.

Eighty-six and five tenths grams (0.294 mole) of 4bmethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-

'ture overnight.

dodecahydrophenanthrene1,4-diol was dissolved in 2,130 g. (2,250 cc.)(21.7 moles) of cycl'ohexanone, and 2,250 cc. of benzene. To thissolution was added 86.5 g. (0.424 mole) of aluminum isopropoxide, andthe whole was then set to refiux for 12 hours. At the end of this time25 cc. of water was added. The coagulated aluminum hydroxide thus formedwas filtered off. The filtrate was concentrated and dried in vacuo,leaving a residue which, on trituration with petroleum ether, gave thecrude crystalline product 4b-methyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene- 4-ol-1-one. It canbe purified by recrystallization from acetone and melts at 219-220 C.

To 10.0 g. of 4b-methyl-7-ethylenedioxy-1,2,3,4,4a,4b, 5,6,7,8,10,l0adodecahydrophenanthrene 4 ol 1- one dissolved in ml. of benzene and 70ml. of t-butyl alcohol was added, at reflux temperature, 1.5 equivalentsof 1 M potassium t-butoxide in t-butyl alcohol, and 20 ml. of a 1:1solution of methyl iodide in benzene. After 30 minutes of refluxing, thesolution was quenched with water, concentrated in vacuo, and theconcentrate extracted with CHCl The CHCl extract was dried and thesolvent removed in vacuo. Fractional crystallization of the crystallineresidue from ethyl acetate, yielded the desired product,2,4b-dimethyl-7-ethylenedioxy-1,2,3, 4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4- ol-l-one, M. P. 189-192 C.

A solution of 3.12 g. of 2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene- 1-one-4-ol (M. P.189192 C.) in 30 cc. of pyridine was combined with 3.1 g. of chromiumtrioxide in 30 cc. of pyridine. The reaction flask was stoppered, thecontents mixed thoroughly and allowed to stand at room tempera- Thereaction mixture was poured into water and extracted with three portionsof benzene-ether (1:1) with filtration through diatomaceous earth tobreak the emulsions. After washing with water, the combined organicsolution was dried over anhydrous magnesium sulfate and concentratedwith final drying of the residue under vacuum. Crystallization fromether gave crystalline 2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 1,4 dione M. P. 145 C.Chromatography over alumina and elution' with petroleum ether-ether(8:2) gave two purified isomers, M. P. 136 C. and 152153 C.

A solution of 16.0 g. of crude 2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1,4-dione (M. P.130-145 C. and consisting of a mixture of isomers M. P. 135-136 C. and152153 C.) in 190 cc. of benzene was concentrated to cc. to insuredryness. The solution was then placed under nitrogen, and treatedsuccessively with 16.0 cc. of methallyl iodide and 70 cc. of tertiarybutyl alcohol containing 2.31 g. of dissolved potassium. After standingat room temperature for three hours, the mixture was poured into ether,the ethereal solution washed with water, concentrated to dryness andpurified by chromatography on either acid washed or alkaline alumina,the product being eluted with petroleum ether-ether mixtures. Pure2,4b-dimethyl-2-methallyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene- 1,4-dione was obtained, M. P. 108109 C.

Another isomeric form of this compound having a melting point of 138-139C. was also recovered from the chromatographic column.

A solution of ethyl magnesium bromide (0.1526 in.) was prepared in theusual manner from 3.7 g. of magnesium and excess ethyl bromide in 100ml. of dry ether. A solution of 11.74 g. of ethoxyacetylene (0.165 In.)diluted with dry ether to a total volume of 40 ml. was added graduallyto the ethyl Grignard and stirred until the evolution of ethane ceased.120 ml. of dry benzene was added to dissolve the ethoxyacetylenemagnesium bromide.-

A solution of 27 g. of dry 2,4b-dirnethyl-2-methally1- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-14-dione(stereoisomer of M. P. 108- 109 C.) in 150 ml. of dry benzene was addedrapidly to the stirred Grignard solution. After standing at roomtemperature for two hours the reaction mixture was decomposed by pouringinto ice-water. Enough saturated aqueous ammonium chloride was added tobreak the emulsion which formed. The benzene-ether layer was separatedand washed once with water. The aqueous layer was extracted again with500 ml. of a 1:1 benzeneether solution which, after one water wash, wascombined with the original extract. After drying over anhydrous sodiumsulfate and removal of the latter by filtration, the solvents weredistilled in vacuo. From a solution of the residual oil in ether wereobtained crystals of the stereoisomer of1-ethoxyethinyl-2,4b-dimethyl-2-methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene 1 ol 4 one having anM. P. of 133-134 C.

By using a stereochemical modification of the above starting material M.P. 138-139" C., and treating as above described, there was obtained thestereochemical modification of 1-ethoxyethinyl-2,4b-dimethyI-Z-methallyl7 ethylenedioxy 1,2,3.4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1ol 4 one having an M. P. of 131-132 C.

The 1 ethoxyethinyl 2 allyl 2,4b dimethyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1 ol 4 one used asstarting material in Example 22 hereinabove can be prepared from 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,10adodecahydrophenanthrene 1,4 dione (the preparation of which is describedhereinabove) in accordance with the following procedure:

To a solution containing 4.0 g. of 2,4b dimethyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-l,4-dione dissolvedin 50 ml; or anhydrous benzene is added 20 ml. of a 1 M solution ofpotassium t-butoxide in t-butyl alcohol and 3 ml. of allyl iodide. Theresulting solution is allowed to stand at room temperature for a periodof approximately one hour at the end of which time ice water is added tothe reaction mixture. The aqueous mixture is extracted with ether, andthe ethereal extract is evaporated to dryness. The residual crystallinematerial is dissolved in benzene-petroleum ether, and the solution ischromatographed on acid-washed alumina, and the chromatogram is elutedwith ether-petroleum ether. The solvents are evaporated from thisether-petroleum ether eluate to give 2 allyl 2,4b dimethyl 7ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1,4-dione.

To an ethereal solution of 2.2 molar equivalents of ethoxyacetylenemagnesium bromide was added 37.5 g. of 2 allyl 2,4b dimethyl 7ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene 1,4-dione in 950 ml. of benzene. The reaction mixture was stirred for 2 /2hours at room temperature. It was then poured onto ice water andextracted with ether. The extract was washed with water, dried, andconcentrated in vacuo. The non-crystalline residue was chromatographedon 1.6 kg. of alkaline alumina. With petroleum ether-ether eluates'there was eluted first l-ethoxyethinyl 2 allyl 2,4b dimethyl 7ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one melting at 83.5-85.0" C. after recrystallization fromether-petroleum ether. Further elution gave a stereoisomer of thissubstance, M. P. 159-160 C.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of this No referencescited.

1. THE PROCESS WHICH COMPRISES REACTING $5-11,16,20TR1KETO-PREGNENE3-KETAL WITH AN ORGANIC SULFONYL HALIDE TO PRODUCE $5,16-16 (ORGANICSULFONOXY)-11,20-DIKETO-PREG NADIENE 3-KETAL. 3.$5,16-11,20-DIKETO-(ORGANIC SULFONOXY)-PREGNADIENE 3-KETAL.